AirDuo RespiClick

SIDE EFFECTS

Use Of LABA May Result In The Following

• Serious asthma-related events – hospitalizations, intubations, death [see WARNINGS AND PRECAUTIONS]
• Cardiovascular and central nervous system effects [see WARNINGS AND PRECAUTIONS]

Systemic And Local Corticosteroid Use May Result In The Following

• Candida albicans infection [see WARNINGS AND PRECAUTIONS]
• Immunosuppression [see WARNINGS AND PRECAUTIONS]
• Hypercorticism and adrenal suppression [see WARNINGS AND PRECAUTIONS]
• Reduction in bone mineral density [see WARNINGS AND PRECAUTIONS]
• Growth effects in pediatrics [see WARNINGS AND PRECAUTIONS]
• Glaucoma and cataracts [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience In Asthma

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

In two placebo-controlled, 12-week, clinical studies (Trials 1 and 2) [see Clinical Studies], a total of 1,364 adolescent and adult patients with persistent symptomatic asthma despite ICS or ICS/LABA therapy were treated twice daily with either placebo; fluticasone propionate MDPI 55 mcg, 113 mcg or 232 mcg (ARMONAIR RESPICLICK, hereafter referred to as fluticasone propionate MDPI); or AIRDUO RESPICLICK 55 mcg/14 mcg, 113 mcg/14 mcg, or 232 mcg/14 mcg. Sixty percent of patients were female and 80% of patients were white. The average duration of exposure was 82 to 84 days in the fluticasone propionate MDPI and AIRDUO RESPICLICK treatment groups compared with 75 days in the placebo group. Table 2 displays the incidence of most common adverse reactions in pooled Trials 1 and 2.

Table 2: Adverse Reactions with ≥3% Incidence with AIRDUO RESPICLICK, and More Common than Placebo in Subjects with Asthma (Trials 1 and 2)

Adverse Reaction	Fluticasone Propionate MDPI 55 mcg (n=129) %	Fluticasone Propionate MDPI 113 mcg (n=274) %	Fluticasone Propionate MDPI 232 mcg (n=146) %	AIRDUO RESPICLICK 55 mcg/14 mcg (n=128) %	AIRDUO RESPICLICK 113 mcg/14 mcg (n=269) %	AIRDUO RESPICLICK 232 mcg/14 mcg (n=145) %	Placebo (n=273) %
Nasopharyngitis	5.4	5.8	4.8	8.6	4.8	6.9	4.4
Oral candidiasis*	3.1	2.9	4.8	1.6	2.2	3.4	0.7
Headache	1.6	7.3	4.8	5.5	4.8	2.8	4.4
Cough	1.6	1.8	3.4	2.3	3.7	0.7	2.6
Back pain	0	1.5	1.4	3.1	0.7	0	1.8
*Oral candidiasis includes oropharyngeal candidiasis, oral fungal infection, and oropharyngitis fungal

Other adverse reactions not previously listed (and occurring in <3% of patients and in three or more patients on AIRDUO RESPICLICK) that were reported more frequently by patients with asthma treated with AIRDUO RESPICLICK compared with patients treated with placebo include the following:

Sinusitis, oropharyngeal pain, pharyngitis, dizziness, influenza, rhinitis allergic, respiratory tract infection, rhinitis, nasal congestion, abdominal pain upper, myalgia, pain in extremity, dyspepsia, laceration, dermatitis contact, and palpitations.

Long Term Safety Study

This was a 26-week, open labeled study of 674 patients previously treated with ICS who were treated twice daily with fluticasone propionate MDPI 113 mcg or 232 mcg; AIRDUO RESPICLICK 113 mcg/14 mcg or 232 mcg/14 mcg; fluticasone propionate inhalation aerosol 110 mcg and 220 mcg; fluticasone propionate and salmeterol inhalation powder (250 mcg/50 mcg), or fluticasone propionate and salmeterol inhalation powder (500 mcg/50 mcg). The types of adverse reactions were similar to those reported above in placebo controlled studies.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during post approval use of fluticasone propionate and/or salmeterol regardless of indication. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These events have been chosen for inclusion due to either their seriousness, frequency of reporting, or causal connection to fluticasone propionate and/or salmeterol or a combination of these factors.

Cardiac Disorders: Arrhythmias (including atrial fibrillation, extrasystoles, supraventricular tachycardia), ventricular tachycardia.

Endocrine Disorders: Cushing’s syndrome, Cushingoid features, growth velocity reduction in children/adolescents, hypercorticism.

Eye Disorders: Glaucoma, blurred vision and central serous chorioretinopathy.

Gastrointestinal Disorders: Abdominal pain, dyspepsia, xerostomia.

Immune System Disorders: Immediate and delayed hypersensitivity reaction (including very rare anaphylactic reaction). Very rare anaphylactic reaction in patients with severe milk protein allergy.

Infections and Infestations: Esophageal candidiasis.

Metabolic and Nutrition Disorders: Hyperglycemia, weight gain.

Musculoskeletal, Connective Tissue, and Bone Disorders: Arthralgia, cramps, myositis, osteoporosis.

Nervous System Disorders: Paresthesia, restlessness.

Psychiatric Disorders: Agitation, aggression, depression. Behavioral changes, including hyperactivity and irritability, have been reported very rarely and primarily in children.

Reproductive System and Breast Disorders: Dysmenorrhea.

Respiratory, Thoracic, and Mediastinal Disorders: Chest congestion; chest tightness, dyspnea; facial and oropharyngeal edema, immediate bronchospasm; paradoxical bronchospasm; tracheitis; wheezing; reports of upper respiratory symptoms of laryngeal spasm, irritation, or swelling such as stridor or choking.

Skin and Subcutaneous Tissue Disorders: Ecchymoses, photodermatitis.

Vascular Disorders: Pallor.

DRUG INTERACTIONS

AIRDUO RESPICLICK has been used concomitantly with other drugs, including short-acting beta₂-agonists, and intranasal corticosteroids, commonly used in patients with asthma without adverse drug reactions [see CLINICAL PHARMACOLOGY]. No formal drug interaction trials have been performed with AIRDUO RESPICLICK.

Inhibitors Of Cytochrome P450 3A4

Fluticasone propionate and salmeterol, the individual components of AIRDUO RESPICLICK, are substrates of CYP3A4. The use of strong CYP3A4 inhibitors (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin) with AIRDUO RESPICLICK is not recommended because increased systemic corticosteroid and increased cardiovascular adverse effects may occur.

Ritonavir

Fluticasone Propionate

A drug interaction trial with fluticasone propionate aqueous nasal spray in healthy subjects has shown that ritonavir (a strong CYP3A4 inhibitor) can significantly increase plasma fluticasone propionate exposure, resulting in significantly reduced serum cortisol concentrations [see CLINICAL PHARMACOLOGY]. During postmarketing use, there have been reports of clinically significant drug interactions in patients receiving fluticasone propionate and ritonavir, resulting in systemic corticosteroid effects including Cushing’s syndrome and adrenal suppression.

Ketoconazole

Fluticasone Propionate

Coadministration of orally inhaled fluticasone propionate (1,000 mcg) and ketoconazole (200 mg once daily) resulted in a 1.9-fold increase in plasma fluticasone propionate exposure and a 45% decrease in plasma cortisol area under the curve (AUC) but had no effect on urinary excretion of cortisol.

Salmeterol

In a drug interaction trial in 20 healthy subjects, coadministration of inhaled salmeterol (50 mcg twice daily) and oral ketoconazole (400 mg once daily) for 7 days resulted in greater systemic exposure to salmeterol (AUC increased 16-fold and Cmax increased 1.4-fold). Three (3) subjects were withdrawn due to beta₂-agonist side effects (2 with prolonged QTc and 1 with palpitations and sinus tachycardia). Although there was no statistical effect on the mean QTc, coadministration of salmeterol and ketoconazole was associated with more frequent increases in QTc duration compared with salmeterol and placebo administration [see CLINICAL PHARMACOLOGY].

Monoamine Oxidase Inhibitors And Tricyclic Antidepressants

AIRDUO RESPICLICK should be administered with extreme caution to patients being treated with monoamine oxidase inhibitors or tricyclic antidepressants, or within 2 weeks of discontinuation of such agents, because the action of salmeterol, a component of AIRDUO RESPICLICK, on the vascular system may be potentiated by these agents.

Beta-Adrenergic Receptor Blocking Agents

Beta-blockers not only block the pulmonary effect of beta-agonists, such as salmeterol, a component of AIRDUO RESPICLICK, but may also produce severe bronchospasm in patients with asthma. Therefore, patients with asthma should not normally be treated with beta-blockers. However, under certain circumstances, there may be no acceptable alternatives to the use of beta-adrenergic blocking agents for these patients; cardioselective beta-blockers could be considered, although they should be administered with caution.

Non-Potassium-Sparing Diuretics

The ECG changes and/or hypokalemia that may result from the administration of non– potassium-sparing diuretics (such as loop or thiazide diuretics) can be acutely worsened by beta-agonists, such as salmeterol, a component of AIRDUO RESPICLICK, especially when the recommended dose of the beta-agonist is exceeded. Although the clinical significance of these effects is not known, caution is advised in the coadministration of AIRDUO RESPICLICK with non–potassium-sparing diuretics.

Read the entire FDA prescribing information for AirDuo RespiClick (Fluticasone Propionate and Salmeterol)